Key Protein Keeps New Neurons Headed in the Right Direction

The birth of new neurons throughout life in many brain areas has raised hopes for treating brain diseases by transplanting young, healthy cells into injured or diseased parts of the brain. But it shouldn’t be taken for granted that the replacement neurons will form the right connections, a new study has found.

Neuroscientist Fred H. Gage at The Salk Institute, La Jolla, Calif., and colleague Sebastian Jessberger, now at the Federal Institute of Technology in Zurich, report that neurons deficient in a protein called cdk5 can grow in the wrong direction and set up shop in brain circuits where they don’t belong. The study appears in the Nov. 11 issue of the open access journal PLoS Biology.

The researchers traced the path of key neurons in a part of the brain called the hippocampus, a structure involved in learning, memory and spatial orientation. Ten years ago the Gage lab was first to prove in humans that new neurons are produced throughout life in this region of the brain. The discovery overturned decades of scientific dogma, which held that the production of neurons (known as neurogenesis) did not occur after birth or very early childhood.

The new study also comes as something of a jolt, Gage says. “It was generally assumed that if transplanted neurons didn’t reach the right spot and make the right connections, they would not function and might even die. In our study, neurons missing cdk5 went the wrong way, but survived very well. They did everything they were supposed to do, they just did it wrong,” he says.

Previous research had shown that cdk5 is involved in brain cell development, learning and memory. In the new study, Gage and colleagues used a modified virus to infect specific hippocampal neuron cells with a gene that renders cdk5 non-functional. Many of the cells left the path they should have followed to the part of the hippocampus where they would become full-grown, functioning neurons.

These misdirected cells grew oddly, as well. The antenna-like projections known as dendrites, with which neurons receive signals from other cells, pointed in the wrong direction. The dendrites also had fewer spines (structures where the actual hook-up with other cells is made). Importantly, though, the neurons did integrate into the brain cell networks they reached—which could possibly interfere with normal information processing, according to Gage.

The study sounds a cautionary note for regenerative medicine, which uses the immature neurons known as stem cells to replace brain cells lost in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, or to replace injured nerve tissue, as in spinal cord injury. “Therapies have to ensure the cells reach the right place to produce the molecular machinery that allows them to integrate correctly,” says Gage. “It’s an intricate dance.”

On the bright side, the study reveals a previously unknown step in the dance, showing the importance of cdk5 in neuronal migration. In addition, even if cells were missing cdk5, some of them still managed to make it to the right destination, and these grew and functioned normally. The altered cells also developed normally when grown in culture; only when reaching the wrong brain area did they have problems.

“It really is location, location, location,” says Gage. “The right location is essential for the cell to function normally—so important that it can even correct the inherent deficit in the cell.”

Li-Huei Tsai, a neurobiologist at the Massachusetts Institute of Technology and the Howard Hughes Medical Institute, finds the study intriguing. “It teases out the importance of cdk5 in regulating the development of dendrites and spines,” she says. “This may provide a clearer picture of many disorders in which normal circuits are disrupted, such as epilepsy, autism and some types of mental retardation.”

Gage adds that the finding may shed light on another aspect of neurodegenerative disease: why diseased cells are not replaced accurately by what is now known to be a normal, ongoing process of neurogenesis. “It’s possible that normal variations of cdk5 may interact with age and disease to make some people more vulnerable to neurodegenerative disorders than others,” he says.